Problematic alcohol and nicotine use may arise in response to stress and negative life events, but may also be influenced by genetic factors. One genetic risk factor is sensitivity to alcohol and nicotine, including sensitivity to the more positive, stimulant effects and to depressant effects that may curb intake. We have identified genetic regions harboring genes that influence sensitivity to nicotine and alcohol, and find some overlap in those regions that influence sensitivity to these highly co-abused drugs. There is also some overlap of these regions with genetic regions that appear to control alcohol consumption. Differences in drug sensitivity (e.g., decreased sensitivity to negative effects or increased sensitivity to positive effects) may lay a foundation for further drug experimentation, leading to behavioral and physiological changes that influence whether excessive use develops and is maintained. Our previous results indicate that cholinergic processes (both nicotinic and muscarinic) are important in determining sensitivity to alcohol, and that genetically-determined differences in alcohol and nicotine sensitivity are genetically correlated. The current work will build on our previous genetic and pharmacological investigations and will additionally explore nicotine/ethanol interactions by examining patterns of gene expression that are specific for each drug, as well as those that are shared in common. The key questions that will be addressed are: 1. Are nicotinic cholinergic factors associated with alcohol sensitivity, a risk factor for problem alcohol use? 2. Are muscarinic cholinergic factors associated with alcohol sensitivity? 3. Are there common genetic factors that influence sensitivity to alcohol, nicotine, and their combined effects? We will advance our explorations through the use of genetic mouse models, gene expression methods, laser dissection technology, and RNA interference (RNAi) methods for selective gene silencing. We have three specific objectives (SO). SO1 will complete small segment congenic mapping of a QTL for ethanol stimulation on mouse chromosome 9, and advance our examination of the involvement of specific nicotinic acetylcholine receptor subunit genes. SO2 will complete small segment congenic mapping of a QTL for ethanol stimulation on mouse chromosome 2, and advance our examination of specific muscarinic acetylcholine receptor subtype genes and alcohol sensitivity. SO3 will explore the possibility that common genes influence nicotine and ethanol sensitivity, as well as the response to nicotine and ethanol co-administration. These studies will combine behavioral and genetic analyses. Some of the genetic methods to be applied here will be focused on specific genes in QTL regions mapped to ethanol and/or nicotine sensitivity, and others will take a more global look and have the potential for identifying unexpected genetic mediators. PUBLIC HEALTH RELEVANCE: Project Narrative: Relevance of the Proposed Research to Veterans Heath and/or Healthcare Issues Problems with alcohol and nicotine use are prevalent in VA patient populations, and the VA's leadership in substance abuse research is well known. Substance and alcohol abuse affect veterans of all ages and eras. Attention to this problem requires a significant ongoing commitment of VHA resources to direct substance abuse treatment programs that address the complicating effects of substance abuse on other chronic health problems such as hepatitis C, HIV/AIDS, cancers, and heart disease. In FY06, 355,000 veterans who presented at VA health facilities had substance use diagnoses other than nicotine dependence (Quality Enhancement Research Initiative [QUERI] Substance Use Disorders Fact Sheet, May 2008; www.hsrd.research.va.gov/queri). The most prevalent psychiatric disorders reported by male vietnam war era veterans [1] include alcohol abuse and/or dependence (54% lifetime) and nicotine dependence (48% lifetime). Substance abuse, including alcohol use disorders, ranks in the top three diagnoses in the VA healthcare system (VA Research Currents, January 2007). Soldiers returning from the Iraq War frequently report alcohol concerns [110]. Genetic similarity at the level of linkage and sequence between the mouse and human ensures that the genes we identify to be of importance to addiction-related traits can be identified and examined for a role in human alcohol and nicotine sensitivity and abuse. Further, our investigations are likely to render mechanisms that can be translationally studied in VA and other clinical populations.